Sodium hydride → Cevipabulin

HRID 28409Notes

Reaction equation

HRID 28409 reaction equation
[H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19](F)=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1>CS(C)=O.C(OCC)(=O)C>[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:8][CH2:7][CH2:6][CH2:5][NH:4][CH3:3])=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:29])([F:30])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 101489863-(Methylamino)-1-propanolHCID 119750435-chloro-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine

Product 1

HCID 11488110CevipabulinYield 40.3%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To sodium hydride (60% in mineral oil, 2.3 g, 57.6 mmol) in 20 mL of dimethylsulfoxide at room temperature is added a solution of 3-(methylamino)propan-1-ol (5.14 g, 57.6 mmol) in 10 mL of dimethylsulfoxide. The solution is stirred at room temperature for 1 h, and 5-chloro-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine (5.7 g, 14.4 mmol) is added. The mixture is heated at 60° C. for 3 h, and cooled to room temperature. The reaction mixture is diluted with ethyl acetate, and washed with water and saturated sodium chloride. The organic layer is dried over magnesium sulfate, and concentrated to a residue. The residue is triturated with small amount of acetone, then hexanes, and chromatographed over silica gel, eluting with a gradient of 100% ethyl acetate to 100% methyl alcohol. Concentration provides 5-chloro-6-{2,6-difluoro-4-[3-(methylamino) propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a white solid (2.7 g). MS: m/z 465.1 (M+H).

Workup

  1. temperatureThe mixture is heated at 60° C. for 3 h
  2. temperaturecooled to room temperature
  3. washwashed with water and saturated sodium chloride
  4. dry with materialThe organic layer is dried over magnesium sulfate
  5. concentrationconcentrated to a residue
  6. customThe residue is triturated with small amount of acetone
  7. customhexanes, and chromatographed over silica gel
  8. washeluting with a gradient of 100% ethyl acetate to 100% methyl alcohol
  9. concentrationConcentration

Sources & evidence

ORD record
ord-114cf71f34484936a7ecc3d10c24dc98
Source dataset
uspto-grants-2008_09
Patent number
US07419982B2

Reaction notes

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